HIV-1, the predominant cause of AIDS in humans, is unable to replicate in most non-human species. Therefore, the most practical animal model of human AIDS consists of infection of rhesus macaques with SIVMAC or chimeras derived from SIVMAC that encode the HIV-1 envelope (SHIV). However, the usefulness of these models is limited by the fact that HIV-1 and SIVMAC are distinct viruses. Based on an understanding of species-specific restriction factors that we have acquired during the past few years, we have generated a recombinant viruses, named simian tropic HIV (stHIV), that are almost entirely derived from HIV-1 but can replicate very efficiently in primary rhesus and pigtailed macaque cells in vitro. Our preliminary data show that stHIV variants are able to replicate at low levels in rhesus and high levels in pigtailed macaques in vivo. The aims of this proposal are to generate improved derivatives of stHIV with enhanced ability to replicate and cause AIDS in animals and to use these viruses to study HIV-1 pathogenesis in vivo. First, we will expand our very recent findings that an stHIV variant can replicate efficiently in pigtailed macaques and derive a molecular clone of this virus that consistently replicates efficiently in pigtailed macaques in vivo. Based on this virus we will generate R5-tropic variants and initiate mucosal transmission studies. Second, we will reduce the SIVMAC sequences present in stHIV constructs by generating minimally mutated HIV-1 proteins that can confer resistance to macaque restriction factors. Third, we will determine the role of SIVMAC proteins in stHIV replication in rhesus macaques. Finally, we will use the stHIV model to assess the role of HIV-1 accessory proteins in virus replication in vivo. Ultimately, we will generate stHIVs that closely resemble HIV-1 strains that circulate in humans and cause AIDS in an animal model. If successful, these studies should revolutionize the preclinical exploration and development of AIDS therapeutics and vaccines. PUBLIC HEALTH RELEVANCE: HIV-1, the predominant cause of AIDS in humans, is unable to replicate in most nonhuman primate species and current animal models are limited. We have developed novel chimeric viruses based on HIV-1 and are proposing to test their utility as an HIV-1 infection model in monkeys and to generate additional HIV-1-derived viruses. If successful, this proposal will lead to improved animal models for HIV-1 infection and will considerably facilitate the development and testing of drug and vaccine interventions.